PROJECT SUMMARY A major risk factor in the vulnerability to immune disorders is biological sex. In some of the most prevalent immune disorders such as allergy/anaphylaxis, autoimmune disease, and chronic pain disorders, females are at increased risk. Adult sex hormones, such as estrogen, may explain some of the sex differences; however, that many immune disorders exhibit a sex bias in prepubertal children challenges this concept. Our recent published and preliminary studies have uncovered sex differences in the mast cell that may explain female vulnerability or male resilience to many immune disorders. Mast cells are innate immune cells that play a central role as effector cell and orchestrators of the immune response. The fact that many mast cell-associated disorders (Allergy, auto- immune, chronic pain, irritable bowel syndrome) exhibit a sex bias in both childhood and adulthood positions the mast cell as a novel regulator of sex differences in immune diseases. Specifically we have shown that female mast cells possess an increased capacity to synthesize, store and release potent mast cell mediators including histamine, serotonin, proteases, etc. In animal models of IgE-mediated anaphylaxis and psychological stress, female animals exhibited enhanced release of mast cell mediators and more severe pathophysiologic and clinical disease, similar to humans. Moreover our recent preliminary data showed that sex differences in mast cells emerge early in development prior to puberty and thus may explain sex differences observed in children. When and how sex differences in the mast cell increase female vulnerability to immune disorders is unknown. Based on preliminary data, we hypothesize that sexual differences in mast cell phenotype and immune-related disease susceptibility is established early in life by perinatal androgens. In this R21 proposal, we aim to establish the role perinatal sex hormones in sex differences in the mast cell and susceptibility/resiliency to later life immune diseases. Toward this goal, we will 1) identify when in development sex differences emerge in the phenotype of mast cells and 2) identify the contribution of perinatal androgens in mast cell sex differences and disease susceptibility. The exploratory studies proposed in the grant application will represent a major paradigm shift in the understanding of sex and mast cell related immune disorders.